Advances in gold catalyzed synthesis of quinoid heteroaryls

This review explores recent advancements in synthesizing quinoid heteroaryls, namely quinazoline and quinoline, vital in chemistry due to their prevalence in natural products and pharmaceuticals. It emphasizes the rapid, highly efficient, and economically viable synthesis achieved through gold-catalyzed cascade protocols. By investigating methodologies and reaction pathways, the review underscores exceptional yields attainable in the synthesis of quinoid heteroaryls. It offers valuable insights into accessing these complex structures through efficient synthetic routes. Various strategies, including cyclization, heteroarylation, cycloisomerization, cyclo-condensation, intermolecular and intramolecular cascade reactions, are covered, highlighting the versatility of gold-catalyzed approaches. The comprehensive compilation of different synthetic approaches and elucidation of reaction mechanisms contribute to a deeper understanding of the field. This review paves the way for future advancements in synthesizing quinoid heteroaryls and their applications in drug discovery and materials science.


Introduction
Over the past two centuries, signicant research attention has been directed towards quinoid alkaloids, spurred by the isolation of quinine from cinchona tree bark in 1820 and the vaccine from Adhatoda vasica in 1888.2][3][4][5][6][7] Many of these compounds have played crucial roles in medicinal chemistry, materials science, and optoelectronics. 8,9Traditional synthetic methods for quinoline and quinazoline derivatives oen face challenges such as harsh conditions, limited substrates, multistep processes, and waste generation, necessitating innovative approaches. 10Transition metal 11 catalyzed formation of N-heterocycles remains a vibrant research area due to the metal's electron transfer capabilities, availability, and efficiency as catalysts.][14] Because gold has special catalytic properties and is the most electronegative metal in Pauling's scale, it is chosen as a catalyst over other transition metals, 15 underscoring its distinctiveness and importance in catalysis.Advances in homogeneous and heterogeneous catalysis techniques have made gold catalysis a "hot topic" in the realm of organic synthesis.The pioneering work of Hutchings and Haruta in the 1980s laid the foundation for heterogeneous gold catalysis, demonstrating its efficacy in acetylene hydrochlorination and CO oxidation.This catalytic system, characterized by gold nanoparticles supported on various substrates, has found extensive use in industrial processes due to its robustness and efficiency. 16omogeneous gold catalysis had a rise in popularity in the 2000s because of its many reactivities, large selection of gold complexes, simplicity of usage, and moderate reaction conditions.Because of its adaptability, homogeneous gold catalysis has become an important synthetic tool for scientists studying materials, organic, 17 and organometallic chemistry.][20][21][22][23][24][25] Over recent years, gold carbene intermediates formed when an electrophile approached the distal end of an alkenyl gold complex, leading to various transformations, 26 and making gold catalysis highly versatile.The gold-catalyzed generation of gold carbenes from readily available alkynes represents a major advancement in metal carbene chemistry, enhancing the scope and versatility of gold catalysis. 27Similarly, in organic synthesis, a-oxo metal carbenes/carbenoids 28 played a crucial role in enabling complex processes such as cyclopropanation, ylide production, and C-H insertion. 29,30The protodeauration mechanism of various organogold compounds, including gold-alkyl, 31 gold-alkynyl, and gold-allyl species, was also studied. 28,32,33A synergistic gold-iron and gold-palladium 34 catalytic system enabled efficient C-C bond formation and macrocyclization under mild conditions, achieving up to 95% yields with excellent regioselectivity. 35Through gold-catalyzed alkyne hydroboration, a new class of stable four-coordinated benzotriazole-borane compounds was synthesized.These compounds exhibit intense uorescence emission and great stability, making them suitable probes for use in the future. 36,37ome gold catalysts are shown in Fig. 1 which are used to synthesize quinoid heteroaryls.Acting as carbophilic p-Lewis acids, gold catalysts effectively trigger the activation of C-C multiple bonds, leading to the formation of reactive intermediates that facilitate subsequent reactions with diverse partners. 380][41] Previous reviews by our group provided a comprehensive overview of the synthesis pathways for gold complexes 42 and their versatile applications as anti-cancer agents across various therapeutic modalities. 43The recent review underscores the synthesis of quinoid heteroaryl using gold-catalyzed cascade protocols, emphasizing the need to enhance efficiency, expand substrate diversity, and investigate sustainable approaches.Collaboration between synthetic chemists and pharmaceutical researchers is essential for leveraging these advancements in drug discovery.

Synthesis of pseudorutaecarpine (1b)
5][46][47] Developing efficient synthetic methods and assessing their biological activities is crucial for exploring their potential pharmacological applications. 48Wang et al., were synthesized numerous derivatives of pseudorutaecarpine with high yields using a gold-catalyzed selective cyclization and 1,2-shi of N-alkynyl quinazolinone-tethered indoles (Scheme 1A).As the model substrate, N-alkynyl quinazolinone-tethered indole (1a) was chosen, and at room temperature, it selectively produced pseudorutaecarpine (1b).Optimizing ancillary gold ligands revealed JohnPhos as highly effective (96% yield).Employing AgNTf 2 as the Ag(I) salt and CH 3 CN as a solvent alongside JohnPhosAuCl signicantly enhanced yield (92%).The sole use of gold did not yield 1b, affirming the necessity of both catalysts. 49ased on previous studies, [50][51][52] the reaction mechanism for the formation of 1b from 1a involves a cationic gold-catalyzed complex formation activating the alkyne group to yield intermediate A 50,52,53 as shown in (Scheme 1B).Intermediate B is formed by a subsequent 5-exo-dig cyclization that yields iminium/vinyl gold.Intermediate C was produced by a 1,2-shi that yields carbon cation.The catalytic cycle was nished when intermediate D produced pseudorutaecarpine 1b through proton removal and proton-deauration.An analogous route might be reached by directly C2-cyclizing intermediate A. 49

Synthesis of functionalized quinazoline 1 oxide (1e)
Quinazoline 1-oxides remain underexplored in medicinal chemistry despite the parent quinazoline's prominence in drug discovery. 54Synthesis typically involves oxidation, lacking documented general methods for convergent synthesis.6][57][58][59]   trapped, sequential N-O bond cleavage is orchestrated, and C-O and C-N bonds are concurrently formed.There was competition between the addition of heteroatoms within and between molecules to alkynes, as well as between the production of a-imino and a-oxo gold carbenes. 60

Synthesis of polycyclic dihydroquinazolinones (1h)
2][63] Jingyang Sun et al. were synthesized for 1h, in an inert atmosphere, compound 1g and 4 Å molecular sieves (MS) were combined in a ask, followed by the addition of (PPh 3 ) AuCl (10 mol%) and AgOTf.Aer stirring in anhydrous DCE at room temperature for 1.5 hours, the reaction mixture was ltered, and the resulting residue was puried to obtain 1h (85%) as a white solid (Scheme 3).Using (PPh 3 )AuCl/AgOTf at room temperature, the double cascade cyclization of alkynetethered anthranilamides exhibited broad substrate scope and functional group compatibility, yielding dihydroquinazolinones in high yields.Both terminal and internal alkynes smoothly underwent cyclization, with even substrates containing fusedaromatic substituents providing excellent yields.Additionally, while phenyl-substituted internal alkynes required higher temperatures for cyclization, they still produced the desired products, mainly favoring 5-exo-dig cyclization over 6-endo-dig cyclization.Based on literature 64 according to the suggested process, the active gold-catalyst A was produced by scavenging chloride ions during the condensation of the gold-chloride complex precursor with AgOTf.When A coordinated with the alkyne moiety of the substrate, gold p-alkyne complex B was formed.This complex can then be hydrated to create ketone 2B or cyclized to form gold-alkyl complex C. Active catalyst A was renewed by the protodeauration of C, which released enamine intermediate D. The synthesis of double-cyclized product 1h and regeneration of the cationic gold catalyst A was facilitated by the re-coordination of A to enamine intermediate D, which in turn helped the second intramolecular cyclization. 65

Diverse synthesis of quinazoline analogues (1j-l)
Chao Liu et al., initiated their investigation by utilizing 1i as the model substrate, synthesized via Ugi-4CR 66 of 2-ethynylbenzaldehyde, ammonia, salicylic acid, and tert-butyl isocyanide.They conducted screening of various Au catalysts, determining that in situ generated Ph 3 PAuNTf 2 yielded the best results (Scheme 4A).Subsequent experimentation revealed that employing Ph 3 PAuCl with chloride scavengers like AgOTf and Scheme 2 Gold-catalyzed synthesis of quinazoline 1e oxide.
AgBF 4 led to reduced yields, with AgNTf 2 identied as the most efficient catalyst.Substrates derived from 2-ethynyl benzaldehyde, which include an electron-donating dimethyl group, as well as those derived from pent-4-ynal successfully produced quinazolinone analogues 1j-k with impressive yields ranging from 97% to 99%.Additionally, substrates originating from 2-(methylamino)nicotinic acid were also effective in this reaction, yielding quinazolinones 1l at 99%. 67

Synthesis of tetrahydroquinolines (2c)
A ring-opening reaction with alcohols facilitated by Au has been discovered as a result of recent attention being paid to the reactivity of 2-alkynylazetidines.0][71] When N-4nitrophenyl-substituted 2-alkynyl azetidines (2a) were heated, according to Touya Kariya et al., an unanticipated cascade reaction occurred, creating 2c by intramolecular Friedel-Crastype hydroarylation and Au-promoted ring-opening of the azetidine ring 72,73 in a single step (Scheme 5).The rst coordination of a gold complex to the alkynyl moiety resulted in the formation of the gold-alkyne complex A, which causes the cascade reaction of 2a to 2c.With the help of this complex, alcohol may be added nucleophilically to generate enol ether B. Next, the azetidine ring can be opened, allowing for the intramolecular Friedel-Cras type conjugate addition to form enol ether D. D hydrolyzes to produce 2c.As an alternative, d-amino-a,bunsaturated ketone E was produced by hydrolyzing intermediate C with water in the reaction system.This ketone then passes through Au-promoted intra-molecular hydroarylation to form product 2c. 70

Synthesis of tetrahydrobenzo[g]quinolines (2l)
A novel catalyst (C 6 F 5 ) 3 PAuCl, was synthesized and known for its efficacy in the hydroarylation of o-propargyl biaryls (2k).Combining this electron-poor ligand with AgNTf 2 signicantly enhanced the yield of 2l, while AgOTf was less effective (Scheme 9).In another study, 100  protodeauration to form exo intermediate C, which aromatizes rapidly to yield the nal product 2l. 101

Synthesis of C3-indolyl quinoline (2o)
8-Methyl quinoline N-oxide (2m) and 1,2-dimethyl-1H-indole (2n), were employed at various reaction conditions and the desired product 2o was achieved with a 99% yield using MeD-alphosAuCl catalyst (5 mol%) combined with AgOTf co-catalyst (10 mol%) in MeCN at 120 °C for 18 h (Scheme 10).Ph 3 PAuCl and SIPrAuCl catalysts were also effective but less so, yielding 2o at 58% and 56%, respectively but for the synthesis of indole derivatives it was more effective and showed excellent yield.The Friedlander synthesis (FS) enabled the one-step preparation of 3-substituted quinolines from diverse starting materials. 103ang et al., proposed an improved method for synthesizing 3sulfo-quinolines, addressing previous challenges with no selectivity and low yields. 104,105Recent ndings demonstrate alkynyl sulfones as b-keto sulfone substitutes due to regiose-lectivity in reactions, particularly under mild conditions facilitated by gold complexes.sulfonylquinolines (2r) using alkynylsulfones (2p) and 2-aminobenzaldehyde (2q) (Scheme 11).In testing their hypothesis, they examined the reaction between 2p and 2q to produce 2r under varied conditions.Au(III) complexes emerged as the most efficient catalysts, 110 with the highest yield of 2r achieved using 5 mol% PicAuCl 2 in DCE at 60 °C for 3 h, supplemented with 4 Å molecular sieves to capture released water.Gold-catalyzed conditions were successful in annulating various electron-decient alkynes, yielding diversely substituted quinolines at position 3.The proposed mechanism suggests a dual role for the gold-catalyzed-based catalyst, activating both C-C bonds and carbonyl groups to facilitate hydroamination and subsequent cyclization. 111

Synthesis of 4H-pyrrolo[3,2,1-ij]quinoline (3b)
A catalyst-controlled divergent cycloisomerization of indolylynes, yielding complex 9H-pyrrolo[1,2-a]indoles (3c) and 3b from N-propargyl indole substrates (3a) as shown in Scheme 13B.Initial screening using various Au catalysts showed Ph 3 -PAuNTf 2 (ref.116) as effective, yielding products 3b and 3c in 65.5% total yield.While the steric bulky and electron-rich Buchwald-type ligand 117 BrettPhos increased both total yield (71%) and selectivity, the N-heterocyclic carbene ligand IPr 118 produced a comparable total yield with somewhat better selectivity.To explain the chemo-vergence in the cycloisomerizations of 3a that are catalyzed by platinum and gold, a reasonable mechanism was put forward.The cationic [BrettPhosAu] + activated acetylenic link in substrates with 2,3-substitution and 7unsubstitution favors the sterically less hindered 7-position for initial addition, minimizing steric repulsion with bulky ligands. 11911.Synthesis of indolo[1,2-a]quinolin-5(6H)-ones (3g) The compound 3f was synthesized in excellent yields by utilizing the amount of 3e to 2.5 equiv.at a reaction temperature of 65 °C, 3g was obtained with an overall yield of 87% (Scheme 14).To further enhance the yield of 3g, aer complete conversion of 3d (conrmed by TLC analysis aer 3 hours at 65 °C), a solution of HCl in cyclopentyl methyl ether (CPME) was introduced to the reaction mixture to promote the cyclization step.Following an additional 0.5 hours at room temperature, 3g was isolated in 87% yield.Based on observed reactivity and prior literature, [120][121][122][123][124]  A new Au-catalyzed protocol was developed for synthesizing tetrahydroquinolines from N-aryl propargyl amines using tandem intramolecular hydroarylation 72 and transfer hydrogenation reactions.Aer testing various conditions, the researcher optimized the reaction to achieve the highest yield by conducting it in a sealed tube at 65 °C for 24 h under a nitrogen atmosphere, using 1 equivalent of 1a, 1.5 equivalents of HEH, and 5 mol% of XPhosAuNTf 2 in HFIP (Scheme 15).They found that lowering the reaction temperature below 65 °C led to a decrease in yield, which stabilized at this temperature.Based on previous studies [126][127][128] the proposed mechanism involves the formation of complex A through the h Quinoline was hydrogenated in a Teon-lined autoclave equipped with mechanical stirring, temperature control, and pressure monitoring.Quinoline, anhydrous DCM, and the AuNPs/JPS catalyst (5 mol%) were supplied to the reactor under frequent hydrogen ushing, and it was subsequently pressurized with 30 bars of H 2 .At 100 °C, the reaction was continuously stirred for 20 hours before being cooled and depressurized. 131,133or instance, hydrogenation does not take place even aer 20 hours of reaction at 50 °C in DCM at 30 bar hydrogen pressure.However, when the temperature is increased from 70 to 100 °C, the conversion improves signicantly, producing >99% of the product with the pyridine ring hydrogenated.Yet, when the reaction duration is shortened from 20 hours to 10 hours, the reaction remains incomplete with only 77% conversion.Hydrogen pressure was also optimized during this study. 134uinoline hydrogenation was carried out by Jianbo Zhao et al. at 100 °C using a stainless-steel autoclave lled with 3.0 mL of water, 60 mL of quinoline, and 0.1 g of gold catalysts at an H 2 pressure of 2.0 MPa (Scheme 16B).Following completion, ethyl acetate was used to extract the reaction mixture three times while it was cooled.Comparing the 1.2% Au@SBA-15-500 catalyst to the 1.3% Au/SiO 2 -500 catalyst, the former showed better activity, selectivity towards py-THQ, and remarkable sintering resistance up to 800 °C.The mesopores and smallsized gold nanoparticles of SBA-15 were responsible for these properties, which allowed for signicant quinoline derivative adaptability and recyclability.ethanol and 30 mg SBA/AuNP catalyst (0.6 mol% gold) under reux until complete consumption of starting materials (Scheme 16C).Catalyst separation via ltration followed by washing with hot ethanol, and product crystallization and drying under reduced pressure were adopted. 138Product characterization was conducted through NMR analysis in DMSO-d 6 , small gold nanoparticles anchored to SBA-15 via a cationic silsesquioxane coating, allowing high dispersion.The optimal gold amount ensures complete anchoring and conversion into nanoparticles during the reduction process.The SBA/AuNP catalyst signicantly enhances the yield of 2l with rapid reagent consumption in just 20 minutes.Decreasing catalyst load prolongs reaction time.SBA-15 catalyst without gold nanoparticles yields only 40% of 1; Scheme 14 Synthesis and proposed reaction pathways for 3g at optimized reaction conditions.even aer 3 hours.Despite a 10% decrease in yield over 3 consecutive runs, the SBA/AuNP catalyst remains effective with a 70% yield in the 3rd recycling run. 139

Summary and outlook
The recent advancements in gold-catalyzed cascade protocols for synthesizing quinoid heterocycles, spanning 2020 to 2024, signify a transformative leap in organic synthesis.Looking forward, further exploration and optimization of these protocols could focus on enhancing reaction scope, selectivity, and sustainability.The use of gold-catalyzed cyclization in synthesizing complex quinoid scaffolds, oen difficult to achieve through conventional methods, underscores the effectiveness of gold-mediated processes.The rapid advancement of goldcatalyzed reactions in forming quinoid heterocycles presents an opportunity for developing environmentally friendly processes, leading to the production of valuable ne chemicals, natural products, and pharmaceuticals in a sustainable manner.Integrating computational methods could aid in designing novel catalysts and predicting reaction outcomes.Additionally, expanding mechanistic understanding could guide the development of more efficient and predictable synthetic routes.Collaboration between synthetic chemists, computational chemists, and chemical engineers will be crucial for translating these innovations into practical applications.Furthermore, exploring the biological activities of newly synthesized quinoid compounds could uncover novel therapeutic agents.Overall, with continued research and innovation, these advancements hold immense potential for driving progress in both academic and industrial settings, paving the way for the synthesis of diverse quinoid heterocycles with unprecedented precision and efficiency.
Wu, Jiawen et al., studied a gold-catalyzed redox-neutral reaction between 8-methyl quinoline N-oxide (2d) and 3-phenyl propane nitrile (2e) yielded N-acylated 2-aminoquinoline (2f) in high yields (Scheme 6).IPr ligand gold catalyst and AgOTf co-catalyst in THF at 120 °C for 18 h, providing an almost stoichiometric yield.MeDalphos-AuCl and IPr-AuCl catalysts also proved effective, producing 2f in 70% and 90% yield, respectively.The Au-catalyzed redoxneutral reaction begins with s-coordination of the Au cation catalyst to the N atom of nitrile 2e, forming intermediate A. Nucleophilic attack by 2d A leads to B, which undergoes intermolecular cycloaddition to form oxazolidine C. Ring-opening and aromatization yield amidated intermediate D, culminating in the desired C2-amidated quinoline 2f aer protodeauration, a core structure in various bioactive molecules, with good functional group tolerance and simple steps.

Scheme 5
Scheme 5 Experiments for mechanistic consideration and proposed reaction mechanism for 2c.
Scheme 6 Plausible reaction pathway and optimized reaction conditions for the synthesis of 2f.
102 A proposed mechanism for Au-catalyzed selective C3-H functionalization of quinoline N-oxides involves C2-auration forming ortho-Au(I)-activated intermediate A, facilitating nucleophilic C3 attack.This leads to TS-1, promoting C-C coupling to form B. AgOTf counter anion assists in proton abstraction from indole 2n and 2m, yielding C and D, respectively.Subsequent deauration generates the desired C3substituted quinoline product 2o and H 2 O, closing the catalytic cycle.

Scheme 8
Scheme 7 At optimized conditions proposed reaction mechanism for synthesis of 2h.

A
Scheme 10 Synthesis and possible reaction pathways for production of 2o.

125 Scheme 11
Scheme 11 Synthesis and possible reaction route for production of 2r.
Scheme 12 Synthesis and proposed reaction mechanism for 2u at optimized conditions.

Scheme 15
Scheme 15 Synthesis and possible reaction mechanism for 3i at optimized conditions.